tbuckley/cabot-search huggingface dataset:
Clinical characteristics and outcome of 318 families with familial monoclonal gammopathy: A multicenter Intergroupe Francophone du Myélome study
Authors: Charles Dumontet, Delphine Demangel, Perrine Galia, Lionel Karlin, Laurent Roche, Mathieu Fauvernier, Camille Golfier, Marie‐Charlotte Laude, Xavier Leleu, Philippe Rodon, Murielle Roussel, Isabelle Azaïs, Chantal Doyen, Borhane Slama, Salomon Manier, Olivier Decaux, Maroulio Pertesi, Marie Beaumont, Denis Caillot, Eileen M. Boyle, Manuel Cliquennois, Pascale Cony‐Makhoul, Anne‐Violaine Doncker, Véronique Dorvaux, Marie Odile Petillon, Jean Fontan, Bénédicte Hivert, Isabelle Leduc, Cécile Leyronnas, Margaret Macro, Michel Maigre, Clara Mariette, Philippe Mineur, Sophie Rigaudeau, Bruno Royer, Laure Vincent, James Mckay, Emeline Perrial, Laurent Garderet
Journal: American Journal of Hematology (2023)

Abstract Familial forms of monoclonal gammopathy, defined as multiple myeloma (MM) or Monoclonal Gammopathy of Undetermined Significance (MGUS), are relatively infrequent and most series reported in the literature describe a limited number of families. MM rarely occurs in a familial context. MGUS is observed much more commonly, which can in some cases evolve toward full‐blown MM. Although recurrent cytogenetic abnormalities have been described in tumor cells of sporadic cases of MM, the pathogenesis of familial MM remains largely unexplained. In order to identify genetic factors predisposing to familial monoclonal gammopathy, the Intergroupe Francophone du Myélome identified 318 families with at least two confirmed cases of monoclonal gammopathy. There were 169 families with parent/child pairs and 164 families with cases in at least two siblings, compatible with an autosomal transmission. These familial cases were compared with sporadic cases who were matched for age at diagnosis, sex and immunoglobulin isotype, with 10 sporadic cases for each familial case. The gender distribution, age and immunoglobulin subtypes of familial cases were unremarkable in comparison to sporadic cases. With a median follow‐up of 7.4 years after diagnosis, the percentage of MGUS cases having evolved to MM was 3%. The median overall survival of the 148 familial MM cases was longer than that of matched sporadic cases, with projected values of 7.6 and 16.1 years in patients older and younger than 65 years, respectively. These data suggest that familial cases of monoclonal gammopathy are similar to sporadic cases in terms of clinical presentation and carry a better prognosis.
Outcomes of patients with <scp>limited‐stage</scp> plasmablastic lymphoma: A <scp>multi‐institutional</scp> retrospective study
Authors: Brian T. Hess, Anshu Giri, Yeonhee Park, Krina K. Patel, Brian K. Link, Grzegorz S. Nowakowski, Seth M. Maliske, Sonia Fortin, Julio C. Chavez, Hayder Saeed, Brian T. Hill, Alex V. Mejia Garcia, Kami J. Maddocks, Walter Hanel, Nina D. Wagner‐Johnston, Marcus R. Messmer, Brad S. Kahl, Marcus Watkins, Juan Pablo Alderuccio, Izidore S. Lossos, Sunita Nathan, Victor M. Orellana‐Noia, Craig A. Portell, Daniel J. Landsburg, Emily C. Ayers, Jorge J. Castillo
Journal: American Journal of Hematology (2023)

Abstract Plasmablastic lymphoma (PBL) is a rare entity, commonly associated with immunosuppressed states such as human immunodeficiency virus (HIV) infection or solid organ transplant. The clinical course is characterized by high relapse rates and a poor prognosis, leading some clinicians to recommend aggressive frontline therapy. However, a specific review of limited stage (LS) PBL patients is not available to evaluate outcomes and justify treatment recommendations. We performed a retrospective review of LS PBL cases to provide insight into this rare disease. Our cohort consisted of 80 stage I or II PBL patients from 13 US academic centers. With a median follow up of 34 months (1–196), the 3‐year progression‐free survival (PFS) and overall survival (OS) of the entire cohort were 72% (95% CI 62, 83) and 79% (95% CI 70, 89), respectively. The 3‐year PFS and OS of patients treated with frontline chemotherapy alone was 65% (95% CI 50, 84) and 71% (95% CI 56, 89), respectively, compared to 85% (95% CI 72, 100) and 96% (95% CI 89, 100), respectively, in patients treated with combined frontline chemotherapy with radiation consolidation. Our data demonstrate favorable outcomes in LS PBL with no improvements in outcome from aggressive frontline treatment including Hyper‐CVAD or auto‐SCT consolidation. Multivariate regression analysis (MRA) demonstrated improved PFS for patients receiving EPOCH based frontline therapy versus CHOP (HR: 0.23; p = 0.029). Frontline chemotherapy followed by radiation consolidation versus chemotherapy alone appeared to be associated with improved relapse and survival outcomes but did not show statistical significance in MRA.
How to use biomarkers of infection or sepsis at the bedside: guide to clinicians
Authors: Pedro Póvoa, Luís Coelho, Felipe Dal-Pizzol, Ricard Ferrer, Angela Huttner, Andrew Conway Morris, Vandack Nobre, Paula Ramirez, Anahita Rouze, Jorge Salluh, Mervyn Singer, Daniel A. Sweeney, Antoni Torres, Grant Waterer, Andre C. Kalil
Journal: Intensive Care Medicine (2023)
Targeting Epsins to Inhibit Fibroblast Growth Factor Signaling While Potentiating Transforming Growth Factor-β Signaling Constrains Endothelial-to-Mesenchymal Transition in Atherosclerosis
Authors: Yunzhou Dong, Beibei Wang, Mulong Du, Bo Zhu, Kui Cui, Kathryn Li, Ke Yuan, Douglas B. Cowan, Sudarshan Bhattacharjee, Scott Wong, Jinjun Shi, Da-Zhi Wang, Kaifu Chen, Joyce Bischoff, MacRae F. Linton, Hong Chen
Journal: Circulation (2023)

Epsin endocytic adaptor proteins are implicated in the progression of atherosclerosis; however, the underlying molecular mechanisms have not yet been fully defined. In this study, we determined how epsins enhance endothelial-to-mesenchymal transition (EndoMT) in atherosclerosis and assessed the efficacy of a therapeutic peptide in a preclinical model of this disease.
Epidemiologic and Clinical Features of Mpox in Transgender and Gender-Diverse Adults — United States, May–November 2022
Authors: Dawn Blackburn, Nicole M. Roth, Jeremy A.W. Gold, Leah Zilversmit Pao, Evelyn Olansky, Elizabeth A. Torrone, R. Paul McClung, Sascha R. Ellington, Kevin P. Delaney, Neal Carnes, Patrick Dawson
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

As of November 9, 2022, a total of 28,730 cases of monkeypox (mpox) had been reported in the United States,* primarily among adult cisgender men reporting recent male-to-male sexual contact (1). Transgender and gender-diverse persons, who constitute an estimated 0.5% of the U.S. adult population,† face unique health disparities and barriers to care (2-4). However, data on the epidemiologic and clinical features of Monkeypox virus infections in this population are limited (5). CDC analyzed U.S. case surveillance data on mpox cases in transgender and gender-diverse adults reported during May 17-November 4, 2022. During this period, 466 mpox cases in transgender and gender-diverse adults were reported, accounting for 1.7% of reported cases among adults. Most were in transgender women (43.1%) or gender-diverse persons (42.1%); 14.8% were in transgender men. Among 374 (80.3%) mpox cases in transgender and gender-diverse adults with information available on sexual or close intimate contact, 276 (73.8%) reported sexual or close intimate contact with a cisgender male partner during the 3 weeks preceding symptom onset. During the ongoing outbreak, transgender and gender-diverse persons have been disproportionately affected by mpox. Members of this population frequently reported recent sexual or close intimate contact with cisgender men, who might be in sexual networks experiencing the highest incidence of mpox. These findings highlight the importance of tailoring public health prevention and outreach efforts to transgender and gender-diverse communities and could guide strategies to reduce mpox transmission.
Relationship between immunosuppression and intensive care unit-acquired colonization and infection related to multidrug-resistant bacteria: a prospective multicenter cohort study
Authors: Louis Kreitmann, Margot Vasseur, Sonia Jermoumi, Juliette Perche, Jean-Christophe Richard, Florent Wallet, Myriam Chabani, Emilie Nourry, Pierre Garçon, Yoann Zerbib, Nicolas Van Grunderbeeck, Christophe Vinsonneau, Cristian Preda, Julien Labreuche, Saad Nseir
Journal: Intensive Care Medicine (2023)
Human IL-10–producing Th1 cells exhibit a molecular signature distinct from Tr1 cells in malaria
Authors: Chelsea L. Edwards, Susanna S. Ng, Fabian de Labastida Rivera, Dillon Corvino, Jessica A. Engel, Marcela Montes de Oca, Luzia Bukali, Teija C.M. Frame, Patrick T. Bunn, Shashi Bhushan Chauhan, Siddharth Sankar Singh, Yulin Wang, Jinrui Na, Fiona H. Amante, Jessica R. Loughland, Megan S.F. Soon, Nicola Waddell, Pamela Mukhopadhay, Lambros T. Koufariotis, Rebecca L. Johnston, Jason S. Lee, Rachel Kuns, Ping Zhang, Michelle J. Boyle, Geoffrey R. Hill, James S. McCarthy, Rajiv Kumar, Christian R. Engwerda
Journal: Journal of Clinical Investigation (2023)

Control of intracellular parasites responsible for malaria requires host IFN-γ+T-bet+CD4+ T cells (Th1 cells) with IL-10 produced by Th1 cells to mitigate the pathology induced by this inflammatory response. However, these IL-10-producing Th1 (induced type I regulatory [Tr1]) cells can also promote parasite persistence or impair immunity to reinfection or vaccination. Here, we identified molecular and phenotypic signatures that distinguished IL-10-Th1 cells from IL-10+Tr1 cells in Plasmodium falciparum-infected people who participated in controlled human malaria infection studies, as well as C57BL/6 mice with experimental malaria caused by P. berghei ANKA. We also identified a conserved Tr1 cell molecular signature shared between patients with malaria, dengue, and graft-versus-host disease. Genetic manipulation of primary human CD4+ T cells showed that the transcription factor cMAF played an important role in the induction of IL-10, while BLIMP-1 promoted the development of human CD4+ T cells expressing multiple coinhibitory receptors. We also describe heterogeneity of Tr1 cell coinhibitory receptor expression that has implications for targeting these molecules for clinical advantage during infection. Overall, this work provides insights into CD4+ T cell development during malaria that offer opportunities for creation of strategies to modulate CD4+ T cell functions and improve antiparasitic immunity.
Impact of antigenic evolution and original antigenic sin on SARS-CoV-2 immunity
Authors: Muriel Aguilar-Bretones, Ron A.M. Fouchier, Marion P.G. Koopmans, Gijsbert P. van Nierop
Journal: Journal of Clinical Investigation (2023)

Infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and vaccinations targeting the spike protein (S) offer protective immunity against coronavirus disease 2019 (COVID-19). This immunity may further be shaped by cross-reactivity with common cold coronaviruses. Mutations arising in S that are associated with altered intrinsic virus properties and immune escape result in the continued circulation of SARS-CoV-2 variants. Potentially, vaccine updates will be required to protect against future variants of concern, as for influenza. To offer potent protection against future variants, these second-generation vaccines may need to redirect immunity to epitopes associated with immune escape and not merely boost immunity toward conserved domains in preimmune individuals. For influenza, efficacy of repeated vaccination is hampered by original antigenic sin, an attribute of immune memory that leads to greater induction of antibodies specific to the first-encountered variant of an immunogen compared with subsequent variants. In this Review, recent findings on original antigenic sin are discussed in the context of SARS-CoV-2 evolution. Unanswered questions and future directions are highlighted, with an emphasis on the impact on disease outcome and vaccine design.
Canagliflozin primes antitumor immunity by triggering PD-L1 degradation in endocytic recycling
Authors: Ling Ding, Xi Chen, Wenxin Zhang, Xiaoyang Dai, Hongjie Guo, Xiaohui Pan, Yanjun Xu, Jianguo Feng, Meng Yuan, Xiaomeng Gao, Jian Wang, Xiaqing Xu, Sicheng Li, Honghai Wu, Ji Cao, Qiaojun He, Bo Yang
Journal: Journal of Clinical Investigation (2023)

Understanding the regulatory mechanisms of PD-L1 expression in tumors provides key clues for improving immune checkpoint blockade efficacy or developing novel oncoimmunotherapy. Here, we showed that the FDA-approved sodium-glucose cotransporter-2 (SGLT2) inhibitor canagliflozin dramatically suppressed PD-L1 expression and enhanced T cell-mediated cytotoxicity. Mechanistic study revealed that SGLT2 colocalized with PD-L1 at the plasma membrane and recycling endosomes and thereby prevented PD-L1 from proteasome-mediated degradation. Canagliflozin disturbed the physical interaction between SGLT2 and PD-L1 and subsequently allowed the recognition of PD-L1 by Cullin3SPOP E3 ligase, which triggered the ubiquitination and proteasome-mediated degradation of PD-L1. In mouse models and humanized immune-transformation models, either canagliflozin treatment or SGLT2 silencing significantly reduced PD-L1 expression and limited tumor progression - to a level equal to the PD-1 mAb - which was correlated with an increase in the activity of antitumor cytotoxic T cells. Notably, prolonged progression-free survival and overall survival curves were observed in the group of PD-1 mAb-treated patients with non-small cell lung cancer with high expression of SGLT2. Therefore, our study identifies a regulator of cell surface PD-L1, provides a ready-to-use small-molecule drug for PD-L1 degradation, and highlights a potential therapeutic target to overcome immune evasion by tumor cells.
Targeting fatty acid metabolism in glioblastoma
Authors: Jason Miska, Navdeep S. Chandel
Journal: Journal of Clinical Investigation (2023)

Glioblastoma (GBM) is a primary tumor of the brain defined by its uniform lethality and resistance to conventional therapies. There have been considerable efforts to untangle the metabolic underpinnings of this disease to find novel therapeutic avenues for treatment. An emerging focus in this field is fatty acid (FA) metabolism, which is critical for numerous diverse biological processes involved in GBM pathogenesis. These processes can be classified into four broad fates: anabolism, catabolism, regulation of ferroptosis, and the generation of signaling molecules. Each fate provides a unique perspective by which we can inspect GBM biology and gives us a road map to understanding this complicated field. This Review discusses the basic, translational, and clinical insights into each of these fates to provide a contemporary understanding of FA biology in GBM. It is clear, based on the literature, that there are far more questions than answers in the field of FA metabolism in GBM, and substantial efforts should be made to untangle these complex processes in this intractable disease.
Notch1 signaling impairs regulatory T cells during multisystem inflammatory syndrome in children
Authors: Magali Noval Rivas, Moshe Arditi
Journal: Journal of Clinical Investigation (2023)

Multisystem inflammatory syndrome in children (MIS-C) is a rare pediatric inflammatory disorder characterized by immune cell hyperactivation, cytokine storm, and the production of autoantibodies. The mechanisms underlying such immune dysregulation still need to be unraveled. In this issue of the JCI, Benamar et al. demonstrated the critical role of the Notch receptor 1/CD22 (Notch1/CD22) axis in Tregs, which, when activated, impairs Treg functions and promotes inflammation. They showed that the Notch1/CD22 axis contributed to dysregulated immune responses in MIS-C. These findings may have implications for MIS-C and many other inflammatory diseases.
Liver-resident CD8+ T cells in viral hepatitis: not always good guys
Authors: Hendrik Luxenburger, Christoph Neumann-Haefelin
Journal: Journal of Clinical Investigation (2023)

More than twenty years ago, non-HBV-specific CD8+ T cells were found to contribute to liver immunopathology in chronic HBV infection, while HBV-specific CD8+ T cells were noted to contribute to viral control. The role of HBV-specific CD8+ T cells in viral control and the mechanisms of their failure in persistent infection have been intensively studied during the last two decades, but the exact nature of nonspecific bystander CD8+ T cells that contribute to immunopathology has remained elusive. In this issue of the JCI, Nkongolo et al. report on their application of two methodological advances, liver sampling by fine-needle aspiration (FNA) and single-cell RNA sequencing (scRNA-Seq), to define a liver-resident CD8+ T cell population that was not virus specific but associated with liver damage, thus representing hepatotoxic bystander CD8+ T cells.
Type I regulatory T cells in malaria: of mice and men
Authors: Jason Nideffer, Prasanna Jagannathan
Journal: Journal of Clinical Investigation (2023)

Type I regulatory T (Tr1) cells are a population of regulatory CD4+ T cells implicated in the suppression of pathological immune responses across multiple diseases, but a unifying transcriptional signature of Tr1 identity across disease contexts has not been characterized. In this issue of the JCI, Edward, Ng, and colleagues identified a conserved transcriptional signature that distinguished Tr1 (IL-10+IFN-γ+) from Th1 (IL-10-IFN-γ+) cells in human and mouse malaria. This signature implicated genes encoding inhibitory receptors - including CTLA-4 and LAG-3 - and transcription factors - including cMAF. The authors identified coinhibitory receptor expression that distinguished Tr1 cells from other CD4+ T cell subsets. Furthermore, cMAF - and, to a lesser extent, BLIMP-1 - promoted IL-10 production in human CD4+ T cells. BLIMP-1 also played a role in supporting the expression of inhibitory receptors. These findings describe a few key features that seem to be conserved by Tr1 cells across multiple species, disease contexts, and marker definitions.
Cargo selection in endoplasmic reticulum–to–Golgi transport and relevant diseases
Authors: Vi T. Tang, David Ginsburg
Journal: Journal of Clinical Investigation (2023)

Most proteins destined for the extracellular space or various intracellular compartments must traverse the intracellular secretory pathway. The first step is the recruitment and transport of cargoes from the endoplasmic reticulum (ER) lumen to the Golgi apparatus by coat protein complex II (COPII), consisting of five core proteins. Additional ER transmembrane proteins that aid cargo recruitment are referred to as cargo receptors. Gene duplication events have resulted in multiple COPII paralogs present in the mammalian genome. Here, we review the functions of each COPII protein, human disorders associated with each paralog, and evidence for functional conservation between paralogs. We also provide a summary of current knowledge regarding two prototypical cargo receptors in mammals, LMAN1 and SURF4, and their roles in human health and disease.
Macrophages and microglia in glioblastoma: heterogeneity, plasticity, and therapy
Authors: Fatima Khan, Lizhi Pang, Madeline Dunterman, Maciej S. Lesniak, Amy B. Heimberger, Peiwen Chen
Journal: Journal of Clinical Investigation (2023)

Glioblastoma (GBM) is the most aggressive tumor in the central nervous system and contains a highly immunosuppressive tumor microenvironment (TME). Tumor-associated macrophages and microglia (TAMs) are a dominant population of immune cells in the GBM TME that contribute to most GBM hallmarks, including immunosuppression. The understanding of TAMs in GBM has been limited by the lack of powerful tools to characterize them. However, recent progress on single-cell technologies offers an opportunity to precisely characterize TAMs at the single-cell level and identify new TAM subpopulations with specific tumor-modulatory functions in GBM. In this Review, we discuss TAM heterogeneity and plasticity in the TME and summarize current TAM-targeted therapeutic potential in GBM. We anticipate that the use of single-cell technologies followed by functional studies will accelerate the development of novel and effective TAM-targeted therapeutics for GBM patients.
Longitudinal liver sampling in patients with chronic hepatitis B starting antiviral therapy reveals hepatotoxic CD8+ T cells
Authors: Shirin Nkongolo, Deeqa Mahamed, Adrian Kuipery, Juan D. Sanchez Vasquez, Samuel C. Kim, Aman Mehrotra, Anjali Patel, Christine Hu, Ian McGilvray, Jordan J. Feld, Scott Fung, Diana Chen, Jeffrey J. Wallin, Anuj Gaggar, Harry L.A. Janssen, Adam J. Gehring
Journal: Journal of Clinical Investigation (2023)

Accumulation of activated immune cells results in nonspecific hepatocyte killing in chronic hepatitis B (CHB), leading to fibrosis and cirrhosis. This study aims to understand the underlying mechanisms in humans and to define whether these are driven by widespread activation or a subpopulation of immune cells. We enrolled CHB patients with active liver damage to receive antiviral therapy and performed longitudinal liver sampling using fine-needle aspiration to investigate mechanisms of CHB pathogenesis in the human liver. Single-cell sequencing of total liver cells revealed a distinct liver-resident, polyclonal CD8+ T cell population that was enriched at baseline and displayed a highly activated immune signature during liver damage. Cytokine combinations, identified by in silico prediction of ligand-receptor interaction, induced the activated phenotype in healthy liver CD8+ T cells, resulting in nonspecific Fas ligand-mediated killing of target cells. These results define a CD8+ T cell population in the human liver that can drive pathogenesis and a key pathway involved in their function in CHB patients.